Rural and Urban Ecologies of Early Childhood Toxic Lead Exposure: The State of Kansas, 2005 to 2012.

Introduction: No safe detectable level of lead (Pb) exists in the blood of children. Until recently, U.S. Centers for Disease Control and Prevention (CDC) guidelines designated a blood lead level (BLL) ≥ 5 µg/dL as an elevated BLL (EBLL). For the State of Kansas, early childhood blood lead burdens lack reporting in the literature. Methods: Secondary analysis was conducted of passively reported EBLL rates ≥ 5 µg/dL among children ages 0 - 5 years at the zip code-level in Kansas during 2005 to 2012. Data weights using corresponding population estimates were applied to produce statewide outcomes. Results: Statewide estimates of annual testing coverage in Kansas among children ages 0 - 5 years were low (9.7%). Approximately 17,000 children ages 0 - 5 years developed an EBLL ≥ 5 µg/dL each year in Kansas with a 6.9% statewide EBLL rate compared to the national rate of 3.2% for the corresponding years. Significant variations in EBLL rates were found between suburban zip codes compared to urban, urban cluster, or rural at 3.1%, 7.2%, 8.8%, and 10.0%, respectively. Among the worst outcomes in EBLL rates was observed for zip codes in southeast Kansas (13.5%) and rural areas with < 500 persons (15.1%). Conclusions: Young children in Kansas had twice the risk of developing an EBLL ≥ 5 µg/dL compared to the national rate, while higher rates consistently were seen outside of the suburbs and particularly in more rural and less populated areas. At-risk children and troubled areas of toxic lead exposure in the State of Kansas require increased recognition with improved targeting and interventions.

Estimated IQ points and lifetime earnings lost to early childhood blood lead levels in the United States.

There is no safe detectable level of lead (Pb) in the blood of children. Blood lead levels (BLLs) at ages 6-24 months ≥2 µg/dL result in lost grade school intelligence quotient (IQ) points at ages 5-10 years. Black children continue to have the highest BLLs in the United States. Therefore, we examined currently undetermined racial/ethnic disparities in anticipated IQ points and associated lifetime earnings lost to early childhood blood lead. We conducted secondary analysis of infants with blood lead (in µg/dL) measured at ages 12-24 months by the cross-sectional National Health and Nutrition Examination Survey (NHANES) during 1999 to 2010. Nationally-representative estimates were produced using weighted simulation model. A total of 1241 infants were included from the NHANES sample (52% male; mean [SD] age, 18.5 [3.5] months; 25% Black [non-Hispanic], 42% Hispanic [any race], 5% Other/Multiracial, and 29% White [non-Hispanic]) after excluding 811 without BLL determinations. For national outcomes, Black infants experienced approximately 46-55% greater average estimated loss of grade school IQ points from blood lead than Hispanic or White infants (-1.78 IQ points vs. -1.15 and -1.21 respectively) with similar disparities in costs to expected lifetime earnings (-$47,116 USD vs. -$30,393 and -$32,356 respectively). Our estimated nationwide costs of IQ points lost to BLLs during this 12-year period totaled $554 billion ($46.2 billion/year), in which blood lead <5 µg/dL accounted for 74% of this total burden. We report two aspects of the substantial national costs attributable to lead exposure in just the second year of life alone, which disproportionately impact predominately African-American Black infants from continuing legacies of environmental racism in lead exposure. Our findings underscore the remarkably high costs from recognized hazards of blood lead even at the lowest levels and the importance of primary prevention regarding childhood lead exposure.

Blood Mercury Levels in Children with Kawasaki Disease and Disease Outcome.

The risk of ethnic Kawasaki disease (KD) has been proposed to be associated with blood mercury levels in American children. We investigated the blood levels of mercury in children with KD and their association with disease outcome. The mercury levels demonstrated a significantly negative correlation with sodium levels (p = 0.007). However, data failed to reach a significant difference after excluding the child with blood mercury exceeding the toxic value. The findings indicate that KD patients with lower sodium concentrations had a remarkably higher proportion of intravenous immunoglobulin (IVIG) resistance (p = 0.022). Our patients who had lower mercury levels (<0.5 µg/L) had more changes in bacille Calmette-Guerin. Mercury levels in 14/14 patients with coronary artery lesions and 4/4 patients with IVIG resistance were all measured to have values greater than 1 µg/L (while average values showed 0.92 µg/L in Asian American children). Mercury levels had no correlations with IVIG resistance or coronary artery lesion (CAL) formation (p > 0.05). CAL development was more common in the incomplete group than in the complete KD group (p = 0.019). In this first report about mercury levels in KD patients, we observed that the juvenile Taiwanese had higher mercury concentration in blood compared to other populations.

Disparity in Risk Factor Severity for Early Childhood Blood Lead among Predominantly African-American Black Children: The 1999 to 2010 US NHANES.

There is no safe detectable level of lead (Pb) in the blood of young children. In the United States, predominantly African-American Black children are exposed to more Pb and present with the highest mean blood lead levels (BLLs). However, racial disparity has not been fully examined within risk factors for early childhood Pb exposure. Therefore, we conducted secondary analysis of blood Pb determinations for 2841 US children at ages 1-5 years with citizenship examined by the cross-sectional 1999 to 2010 National Health and Nutrition Examination Survey (NHANES). The primary measures were racial disparities for continuous BLLs or an elevated BLL (EBLL) ≥5 µg/dL in selected risk factors between non-Hispanic Black children (n = 608) and both non-Hispanic White (n = 1208) or Hispanic (n = 1025) children. Selected risk factors included indoor household smoking, low income or poverty, older housing built before 1978 or 1950, low primary guardian education <12th grade/general education diploma (GED), or younger age between 1 and 3 years. Data were analyzed using a regression model corrected for risk factors and other confounding variables. Overall, Black children had an adjusted +0.83 µg/dL blood Pb (95% CI 0.65 to 1.00, p < 0.001) and a 2.8 times higher odds of having an EBLL ≥5 µg/dL (95% CI 1.9 to 3.9, p < 0.001). When stratified by risk factor group, Black children had an adjusted 0.73 to 1.41 µg/dL more blood Pb (p < 0.001 respectively) and a 1.8 to 5.6 times higher odds of having an EBLL ≥5 µg/dL (p ≤ 0.05 respectively) for every selected risk factor that was tested. For Black children nationwide, one in four residing in pre-1950 housing and one in six living in poverty presented with an EBLL ≥5 µg/dL. In conclusion, significant nationwide racial disparity in blood Pb outcomes persist for predominantly African-American Black children even after correcting for risk factors and other variables. This racial disparity further persists within housing, socio-economic, and age-related risk factors of blood Pb outcomes that are much more severe for Black children.

Ethnic Kawasaki Disease Risk Associated with Blood Mercury and Cadmium in U.S. Children.

Kawasaki disease (KD) primarily affects children <5 years of age (75%-80%) and is currently the leading cause of acquired heart disease in developed nations. Even when residing in the West, East Asian children are 10 to 20 times more likely to develop KD. We hypothesized cultural variations influencing pediatric mercury (Hg) exposure from seafood consumption may mediate ethnic KD risk among children in the United States. Hospitalization rates of KD in US children aged 0-4 years (n = 10,880) and blood Hg levels in US children aged 1-5 years (n = 713) were determined using separate US federal datasets. Our cohort primarily presented with blood Hg levels <0.1 micrograms (µg) per kg bodyweight (96.5%) that are considered normal and subtoxic. Increased ethnic KD risk was significantly associated with both increasing levels and detection rates of blood Hg or cadmium (Cd) in a linear dose-responsive manner between ethnic African, Asian, Caucasian, and Hispanic children in the US (p ≤ 0.05). Increasing low-dose exposure to Hg or Cd may induce KD or contribute to its later development in susceptible children. However, our preliminary results require further replication in other ethnic populations, in addition to more in-depth examination of metal exposure and toxicokinetics.

Gene-Gene Associations with the Susceptibility of Kawasaki Disease and Coronary Artery Lesions.

Kawasaki disease (KD) is a systemic vasculitis primarily affecting children < 5 years old. Genes significantly associated with KD mostly involve cardiovascular, immune, and inflammatory responses. Recent studies have observed stronger associations for KD risk with multiple genes compared to individual genes. Therefore, we investigated whether gene combinations influenced KD susceptibility or coronary artery lesion (CAL) formation. We examined 384 single-nucleotide polymorphisms (SNPs) for 159 immune-related candidate genes in DNA samples from KD patients with CAL (n = 73), KD patients without CAL (n = 153), and cohort controls (n = 575). Individual SNPs were first assessed by univariate analysis (UVA) and multivariate analysis (MVA). We used multifactor dimensionality reduction (MDR) to examine individual SNPs in one-, two-, and three-locus best fit models. UVA identified 53 individual SNPs that were significantly associated with KD risk or CAL formation (p < 0.10), while 35 individual SNPs were significantly associated using MVA (p ≤ 0.05). Significant associations in MDR analysis were only observed for the two-locus models after permutation testing (p ≤ 0.05). In logistic regression, combined possession of PDE2A (rs341058) and CYFIP2 (rs767007) significantly increased KD susceptibility (OR = 3.54; p = 4.14 x 10(-7)), while combinations of LOC100133214 (rs2517892) and IL2RA (rs3118470) significantly increased the risk of CAL in KD patients (OR = 5.35; p = 7.46 x 10(-5)). Our results suggest varying gene-gene associations respectively predispose individuals to KD risk or its complications of CAL.

Association between Kawasaki disease and autism: a population-based study in Taiwan.

OBJECTIVE: The association between Kawasaki disease and autism has rarely been studied in Asian populations. By using a nationwide Taiwanese population-based claims database, we tested the hypothesis that Kawasaki disease may increase the risk of autism in Taiwan. MATERIALS AND METHODS: Our study cohort consisted of patients who had received the diagnosis of Kawasaki disease (ICD-9-CM: 446.1) between 1997 and 2005 (N = 563). For a comparison cohort, five age- and gender-matched control patients for every patient in the study cohort were selected using random sampling (N = 2,815). All subjects were tracked for 5 years from the date of cohort entry to identify whether they had developed autism (ICD-9-CM code 299.0) or not. Cox proportional hazard regressions were then performed to evaluate 5-year autism-free survival rates. RESULTS: The main finding of this study was that patients with Kawasaki disease seem to not be at increased risk of developing autism. Of the total patients, four patients developed autism during the 5-year follow-up period, among whom two were Kawasaki disease patients and two were in the comparison cohort. Further, the adjusted hazard ratios (AHR) (AHR: 4.81; 95% confidence interval: 0.68-34.35; P = 0.117) did not show any statistical significance between the Kawasaki disease group and the control group during the 5-year follow-up. CONCLUSION: Our study indicated that patients with Kawasaki disease are not at increased risk of autism.

Mercury promotes catecholamines which potentiate mercurial autoimmunity and vasodilation: implications for inositol 1,4,5-triphosphate 3-kinase C susceptibility in kawasaki syndrome.

Previously, we reviewed biological evidence that mercury could induce autoimmunity and coronary arterial wall relaxation as observed in Kawasaki syndrome (KS) through its effects on calcium signaling, and that inositol 1,4,5-triphosphate 3-kinase C (ITPKC) susceptibility in KS would predispose patients to mercury by increasing Ca(2+) release. Hg(2+) sensitizes inositol 1,4,5-triphosphate (IP3) receptors at low doses, which release Ca(2+) from intracellular stores in the sarcoplasmic reticulum, resulting in delayed, repetitive calcium influx. ITPKC prevents IP3 from triggering IP3 receptors to release calcium by converting IP3 to inositol 1,3,4,5-tetrakisphosphate. Defective IP3 phosphorylation resulting from reduced genetic expressions of ITPKC in KS would promote IP3, which increases Ca(2+) release. Hg(2+) increases catecholamine levels through the inhibition of S-adenosylmethionine and subsequently catechol-O-methyltransferase (COMT), while a single nucleotide polymorphism of the COMT gene (rs769224) was recently found to be significantly associated with the development of coronary artery lesions in KS. Accumulation of norepinephrine or epinephrine would potentiate Hg(2+)-induced calcium influx by increasing IP3 production and increasing the permeability of cardiac sarcolemma to Ca(2+). Norepinephrine and epinephrine also promote the secretion of atrial natriuretic peptide, a potent vasodilator that suppresses the release of vasoconstrictors. Elevated catecholamine levels can induce hypertension and tachycardia, while increased arterial pressure and a rapid heart rate would promote arterial vasodilation and subsequent fatal thromboses, particularly in tandem. Genetic risk factors may explain why only a susceptible subset of children develops KS although mercury exposure from methylmercury in fish or thimerosal in pediatric vaccines is nearly ubiquitous. During the infantile acrodynia epidemic, only 1 in 500 children developed acrodynia whereas mercury exposure was very common due to the use of teething powders. This hypothesis mirrors the leading theory for KS in which a widespread infection only induces KS in susceptible children. Acrodynia can mimic the clinical picture of KS, leading to its inclusion in the differential diagnosis for KS. Catecholamine levels are often elevated in acrodynia and may also play a role in KS. We conclude that KS may be the acute febrile form of acrodynia.

ITPKC susceptibility in Kawasaki syndrome as a sensitizing factor for autoimmunity and coronary arterial wall relaxation induced by thimerosal's effects on calcium signaling via IP3.

Recently, a single nucleotide polymorphism (SNP) of the inositol 1,4,5-triphosphate kinase C (ITPKC), rs28493229, was found to passively confer susceptibility for Kawasaki syndrome (KS) and subsequent coronary arterial lesions. This association is believed to be the result of defective phosphorylation of inositol 1,4,5-triphosphate (IP3), which releases calcium from intracellular stores, resulting from reduced genetic expression of ITPKC in carriers of the SNP. Reduced ITPKC activity would increase IP3 levels, and thus, increase calcium release. We hypothesized that an environmental agent which influences IP3-mediated calcium release is potentiated by the ITPKC SNP. This led us to an attractive candidate, thimerosal, an organomercurial medical preservative still used in several pediatric vaccines. Thimerosal is well-known to sensitize IP3 receptors via its induction of oxidative stress, resulting in enhanced release of intracellular calcium with distinctive consequences for various cell types. Dysregulated calcium signaling in T cells and other immune cells can result in autoimmunity, while hyperpolarization of vascular smooth muscle cells secondary to the stimulation of calcium-activated potassium channels can result in increased vascular permeability and arterial relaxation. We propose that ITPKC susceptibility in KS is related to its synergy with environmental triggers, such as thimerosal, which alter calcium homeostasis and promote oxidative stress. Therefore, carriers of the ITPKC SNP are more susceptible to thimerosal-induced autoimmunity and coronary arterial lesions observed in KS. This would explain why only a susceptible subset of children develops KS although pediatric thimerosal exposure is nearly universal due to vaccination. As was experienced with the infantile acrodynia epidemic, only 1 in 500 children developed the disease although pediatric mercury exposure was nearly ubiquitous due to the use calomel teething powders. This hypothesis also mirrors the current leading theory for KS in which a widespread infection only induces the disease in susceptible children. We conclude that KS may be the acute febrile form of acrodynia.